Monday, March 15, 2010

I encountered Nest making and oxytocin comparably promote wound healing in isolation reared rats [1] while reading about how stress affects wound healing, and it drew me in with its lure of drawing connections between nest making and oxytocin. Oxytocin does a lot of things in the body, but what this paper was interested in was its participation in social bonding. You all must already know the coolest story about oxytocin, the story about the two species of voles. The species are almost identical. One species mates for life, one doesn’t. The one that does has more receptors in its brain for oxytocin than the one that doesn’t.[2]

Because of the promise of learning more about oxytocin, I chose this paper for my second and final journal club presentation. The second time is a lot less scary than the first, I learned, and preparation goes faster.

This paper took a while to get to oxytocin, so let me start at the beginning. The authors had run three separate experiments which the paper covered. In the first study, Assessment of wound healing due to Nestlet treatment, they gave some rats a burn on their backs. (It was a pretty serious burn; two of the rat pups died of shock after receiving it.) Then they put them into three groups. One group of rats lived in sets of three (“group housed”). One group of rats lived alone (“isolation housed”). And one group of rats lived alone, but were given Nestlets, which are little cotton squares which can be used to make nests. They compared the healing rates of the three groups. The group housed rats healed the fastest; the isolation housed rats which had Nestlets to use to make nests healed almost as fast (statistically there was no significant difference); and the isolation housed rats without Nestlets healed most slowly.

They asked themselves: why does nest making help rats heal better? It seems like the mechanism has to be central (in the brain, rather than in the rest of the body), since a nest is really environmental enrichment. In their second experiment, Time series analysis of wound healing and comparison of wound healing with Nestlets to wound healing with oxytocin, they repeated their first experiment, but this time with a fourth group of rats: isolation housed rats who were injected with oxytocin once a day for several weeks. Why oxytocin? The idea seemed to be that rats build nests together, and if a rat lives alone, building a nest is still somehow a social act. Since oxytocin is released during social bonding, a dose of oxytocin might theoretically substitute for having other rats around or for nest building. And indeed, the rats given oxytocin healed faster, with rates similar to the rates of rats given Nestlets.

Finally, in Assessment of behavior and brain changes due to Nestlet administration, they had four groups of rats: group housed rats without Nestlets; group housed rats with Nestlets; isolation housed rats with Nestlets; isolation housed rats without Nestlets. No rats were burned in this experiment. They demonstrated gene expression changes (mRNA changes) in the brains of rats given Nestlets, and demonstrated behavior changes (decreased hyperactivity in an “open field test”).

They conclude by suggesting that Nestlets do affect wound healing rates; these changes seem to happen because of changes in the brain (though that isn’t proven); and this particular model of wound healing and Nestlet administration might be a good model for studying stress impairment of physical health in humans.

I had gone into this paper enthusiastically, because oxytocin is probably my favorite hormone. I came out the other end bothered on several levels, but decided to present the paper at journal club anyways, because it seemed like a good exercise. The attendees seemed as bothered by the paper as I was, and contributed more issues with it than those I’d come up with; actually, the presentation felt really enjoyable to me as a result.

What bothered me? To start, why were the rats not given any analgesics at all? Perhaps the researchers felt that pain killers would have confounded their study design in some way, but I would have been interested to know what way. As it stood, I wondered if they simply hadn’t thought of it.

Can you really say that the effects of nest making are centrally mediated (take place in the brain) just because they are similar to the effects of oxytocin? Can you even say that the effects of nest making are related to the effects of social interactions? No, you cannot. Perhaps the tool used here for measuring rate changes in wound healing was so insensitive that any number of changes would look similar. Perhaps the changes were in fact very similar but caused by very different things. (One possibility proposed by someone at journal club: the rats which were able to nest improved because the nests helped them keep warm better, something which group housed rats use each other to do.) To their credit, the authors of this paper did state that they hadn’t proven that the effects of Nestlets were centrally mediated or even related to the effects of oxytocin administration. But if they knew that their study wasn’t going to answer that question, why include the oxytocin group at all? Or, if they really were interested in comparing the two mechanisms, why not include an oxytocin group in the experiment in which they looked at behavior changes and mRNA changes in the brain?

The studies certainly did demonstrate that oxytocin administration improves wound healing in isolation reared rats. But does this have to do with the fact that oxytocin is associated with bonding? It might have been interesting to see if oxytocin administration improved wound healing in group housed rats as well.

The studies also demonstrated that providing Nestlets does improve healing rates in isolation housed rats. However, one rat researcher at journal club pointed out that, in fact, they couldn’t even say that “nest building” caused the improvement. Perhaps it was just the exercise of moving the Nestlets around the cage. She suggested a control group which was given exercise wheels.

The suggestion that this model could be useful to study the physical effects of stress in humans gave me pause, as well. Different kinds of stress have different effects. This kind of social isolation stress isn’t necessarily going to affect a human the same way some other kind of stress might, like job-related stress. In fact, one journal club attendee pointed out that the slower wound healing rates in the isolation housed rats might have less to do with social isolation stress, and more to do with the fact that group housed rats are able to lick each other’s wounds. (None of us knew if rats actually did that, though.)

As a veterinary student, I was also a little saddened by the fact that this paper was never placed by its authors into the context of laboratory animal medicine. Though the purpose of the paper was to illustrate a model that is useful for human medicine, I felt at least a sentence could have been devoted to explaining the context of enrichment for laboratory animals and why it is important.

At the end of the paper, the authors explained some future directions for their research, including giving oxytocin antagonists to rats with Nestlets. This would prevent oxytocin from acting in those rats. If the effects of the Nestlets were blocked in those rats (i.e., if their wound healing slowed), then we might conclude that oxytocin had something to do with the mechanism of Nestlets’ effects. That would be an interesting next step and would definitely clarify the Nestlet/oxytocin relationship, if there is one. I wish that they had waited to publish this paper until they could include those findings; as it is, the paper felt somewhat incomplete.

We talked a little bit about the journal that this paper was published in: PLoS ONE, an open access journal. One attendee felt that open access journals are likely to publish lower quality papers. I hope that’s not actually true, since I believe open access to be important. If this paper weren’t open access, I wouldn’t be able to provide a link to its full text in this blog post!

Of course, the paper did have some interesting things to say. Nest making improves wound healing in socially isolated rats. That’s interesting! (But we don’t really have any idea why it does this, at least not based on this paper.) Oxytocin also improves wound healing in socially isolated rats, which I find even more interesting. I’m curious whether oxytocin has been used in wound healing experiments in the past. I know that research has suggested in the past that happily bonded people are healthier (though I don’t know anything about this field and therefore hesitate to try to find a reference for this assertion — if you have a good one, let us know in the comments). I’ve always wondered why. Do people living alone find taking care of themselves harder? They might be more likely to have trouble getting to the hospital, or lack caretakers when they’re ill, or just lack someone to tell them “You’re sick, go to bed.” This study suggests that loneliness might actually affect health more directly. Of course, the complete social isolation these rats experienced might have different effects from the milder isolation of someone who lives alone but works in an office. And healing from burn wounds is not the same thing as general health. It’s still food for thought.

I was definitely dissatisfied with this paper, but the presentation was fun. The attendees felt engaged and interested. I hadn’t realized before how useful it can be to present a paper that you have some issues with. It’s not something I’d do every time, but it’s a useful trick to know.

The bacterial zoo in your bowel: “Who knows what revelations lurk within the poo of other nations?” I love the idea that I am a planet on which (well, inside which) live billions of tiny life forms in their various ecosystems. This is what one of my professors referred to as “dark side of the moon stuff” -- we know so little about what’s normal for the organisms living inside us.

Friday, March 12, 2010

This afternoon was the white coat ceremony for the class of 2011 at my vet school. I went through the first two years of didactic material with the class of 2011; then they continued on to third year while one classmate and I entered our research year. She and I will join the class of 2012 for our third year next year, while the class of 2011 spend their fourth and final year (a fifteen-month year) in clinics. The white coat ceremony marks the end of their three didactic years and the beginning of their clinical training.

It’s a funny time. There is a several week pause between the last of the exams and the beginning of clinics, during which you take some elective classes or just sleep a lot. It feels like vacation, but you spend most of it panicking about starting clinics. Will I make a fool out of myself? Will I survive on so little sleep? Will I lose all my friends because I won’t have time to see them for fifteen months? (The advice of the fourth year student who spoke at the ceremony: Eat whenever you can. Sleep whenever you can. Don’t make weekend plans.) The ceremony reminded me a little of orientation day at the beginning of first year. We were all so proud to have made it, and so terrified of what was to come.

I was deeply proud of my classmates, and a little sad to know I could have been with them but had chosen not to be. I’m looking forward to working with them in the hospital, as they replace the current senior students (who will be on off campus electives from now until graduation) and I continue my research. It is so strange to think that this is where I’ll be in another year.

Thursday, March 4, 2010

I don’t think there’s anything inherently wrong with breeding purebred dogs. We breed dogs for work, for beauty, for good companionship, and breeding different kinds of dogs for different kinds of jobs is a good idea. I do believe, however, that many breed standards dictate physical limitations which are simply unhealthy for dogs.

There are the obvious ones. Dogs bred to have very flat faces (pugs, bulldogs) simply don't have enough muzzle to breathe with. These dogs are more likely to die of respiratory problems — they have, in fact, been known to simply keel over with no warning. There are the less obvious ones, too. Giant breed dogs are highly prone to gastric dilatation and volvulus (GDV), a frequently lethal condition in which the stomach twists and expands. (Great Danes are so prone to GDV that their owners sometimes opt to have a gastropexy, in which the stomach is stapled down so that it can’t twist, performed prophylactically.) There’s some debate about why Danes are particularly prone to GDV: the depth of their chests? Something about their metabolism due to their large size? But we are sure that large, deep chested dogs are more prone to the problem, and we strongly suspect a causal link.

Personally, I see a difference between issues of this kind, which are tied to the breed standard, and more coincidental problems. My chosen breed, the golden retriever, is prone to cancer. This doesn’t have anything particularly to do with what makes them goldens. It is presumably just some bad genetics that got locked in as part of creating a highly homogeneous population of animals. The trait isn’t tied to what we think of as breed characteristics; theoretically, we could someday breed this cancer-factory trait out of goldens without changing the way they look or act. Flat-faced dogs, on the other hand, are going to have breathing problems until we breed them to be a little less flat-faced.

I hear people lumping the two problems together, though. When a responsible owner is choosing a breed of dog to live with, one of the appropriate things to do to is to read up on potential health problems. then decide if you can live with those problems. It surprises me to see people lumping “respiratory problems with pugs” in with “heart disease in King Charles Cavalier Spaniels.” We choose to breed respiratory problems into the pug. We know exactly what to do to breed it back out. People who choose to purchase dogs with these sorts of preventable physical defects are supporting the problem.

That sounds harsh, so let me add that I recognize that people don’t see it that way. People buy pugs because they are nice dogs, and low-energy dogs, and have cute baby faces. They don’t think of these physical problems as things that are easy to breed out. They think of them as just another problem associated with a particular breed. That’s where I feel veterinarians could do more to educate the public. Veterinarians as a group seem to be cautious about giving value judgements to people. They don’t want to drive their business away (and who can blame them?). But if veterinarians are truly acting as the advocates of animals who cannot advocate for themselves, I believe they should do more to teach people that not all breed problems are hard to solve. Some just require us to value the health of the animal more than what it looks like.

I do sympathize with the love of a particular breed. I love giant breed dogs. Whenever I interact with one in the hospital, I go all gooey. Recently I enrolled a Great Dane in my study, and that was a good night for me, getting to handle a dog larger than some ponies. But I will never buy a giant breed puppy. As much as I love them, I believe we need to reevaluate whether it is ethical to breed dogs that large. I know other dog lovers might make similar decisions, if they better understood the implications of the standards of their preferred breeds.

Dog breeders should select dogs for health, and choose not to breed to standards which are inherently unhealthy.

Breed clubs should advocate for changes in breed standards, such that standards no longer describe inherently unhealthy physical limitations.

Veterinarians should offer more judgements to their clients about the kinds of physical limitations it is morally acceptable to support. Perhaps the AVMA could work with breed clubs to help them identify breed standards which would benefit from change.

American Humane and Cesar Millan have met to discuss the differences between their two camps of dog training methods. A board member of American Humane provides us with an urbane report in which both sides of the debate are recognized. I really appreciate this kind of reporting! I agree with many of the points made in this opinion post, but am not sure its tone is as constructive.

About the Dog Zombie

Jessica Perry Hekman, DVM, MS is fascinated by dog brains. She is a PhD student at the University of Illinois, training in a genomics lab which studies a population of tame foxes. Her interests include the stress response in mammals, canine behavior, canine domestication, shelter medicine, animal welfare, and open access publishing. She is also the Technical Director of ScienceSeeker. You may email Jessica at jph at dogzombie dot com. All opinions expressed here are her own.

For the animal shall not be measured by man… They are not brethren, they are not underlings: they are other nations, caught with ourselves in the net of life and time, fellow prisoners of the splendor and travail of the earth. (Henry Beston)